Overall goal of this application is to advance our understanding of ACE2 biology in the lung, to explore a novel link between ACE2 activity and the interferon-?-mediated compromised innate immunity in IAV and subsequent bacterial lung infection, and to lay the groundwork for a new strategy to prevent and treat lethal IAV-bacterial coinfection by manipulating ACE2 activity. Infection with secondary bacterial pathogens is the primary cause of excess mortality during influenza A virus (IAV) outbreaks. Novel therapies that modulate host immunity are urgently needed. Moreover, compelling evidence indicates that the immune defects caused by IAV infection are responsible for the severe secondary bacterial lung infection. These include impaired neutrophil influx due to sustained desensitization and the induction of an immune-suppressive state of the lung. The renin-angiotensin system (RAS) is constitutively activated to maintain blood pressure and to mount a host defense to invading microbes. However, overactive RAS facilitates exacerbated inflammatory response, while repressive RAS curbs host defense. Thus, regulation of optimal RAS signaling may represent a novel therapeutic strategy in a bacterial lung infection. Angiotensin-converting enzyme 2 (ACE2) is a potent negative regulator of the RAS activation. Our preliminary studies in a mouse model of IAV-bacterial coinfection indicate that pulmonary ACE2 is dynamically regulated during IAV infection and peaked around 6 dpi. Interestingly, the IAV induced interferon- ? induces ACE2 expression. We also find that the elevated pulmonary ACE2 activity at the time of secondary bacterial infection mitigates neutrophilic inflammation and increases the severity of the secondary bacterial infection. The observation raises the possibility that the IAV infection induced ACE2 activity, partially by interferon- ?, predispose the mice to secondary bacterial lung infection by attenuating neutrophilic inflammatory response. Our overall hypothesis is that is that ACE2 plays a pivotal role in the IAV induced-IFN- ? mediated immune compromise, thus contributes to the pathogenesis of secondary bacterial lung infection post IAV, and that optimal strategy to manipulate active ACE2 will improve the outcome of IAV-bacterial coinfection. We propose the following aims:
Aim1. To investigate the role and mechanism of IFN- ? induced pulmonary ACE2 in IAV-bacterial coinfection. manipulate active ACE2 will improve the outcome of IAV-bacterial coinfection.
Aim2. To elucidate the mechanisms through which pulmonary ACE2 modulates neutrophil influx in IAV-bacterial coinfection.
Aim3. To evaluate the preventive and interventional strategies to IAV-bacteria co-infection by monitoring serum and manipulating pulmonary ACE2 activity. These studies will make a significant conceptual advance and pre-clinical insight by defining the role and therapeutic potential of ACE2 in IAV-bacterial lung disease.
The current proposal seeks to understand why and how influenza virus lung infection induces ACE2 expression and activity, and in turn facilitates the compromised immune response to secondary bacterial lung infection. We will also try to test the potential preventive and therapeutic usage of ACE2 as a biomarker and clinical reagent.